Viral genetic and epigenetic factors associated with human cytomegalovirus disease among immunocompromised patients in Malaysia

Cytomegalovirus (CMV) infection poses significant risks to immunocompromised patients, including renal transplant recipients, haematopoietic stem cell transplant (HSCT) recipients, and individuals with HIV. This study addressed critical knowledge gaps surrounding CMV infection in Malaysia, focusing on viral genetic and epigenetic factors associated with CMV disease. A comprehensive assessment revealed high prevalence rates among renal transplant (65.1%), HSCT (78.3%), and HIV (75.7%) recipients, with CMV viral load consistently correlating with disease severity. Malays constituted the majority affected group, with no significant gender preference. Primary diagnoses, including glomerulonephritis, hypertension, diabetes mellitus, and acute lymphoblastic leukaemia, varied among study populations, underscoring the burden of CMV infection and the need for tailored monitoring strategies. Notable risk factors included CMV serological status combinations (D+/R- and D+/R+), immunosuppressive regimens containing anti-thymocyte globulin (ATG) or mycophenolate with prednisolone, and comorbidities such as diabetes mellitus. These diverse risk profiles highlight the complexity of CMV management. Genetic variations in CMV glycoproteins were explored to assess associations with CMV disease. Mixed genotype infections were prevalent (51.8% in renal transplant, 52.7% in HSCT, and 62.5% in HIV patients), with gB1-gB2 as the predominant combination. While no significant association between genotype multiplicity and disease severity was observed in transplant recipients, HIV patients with mixed-genotype infections had a markedly higher rate of severe disease (60.7% vs 25.0% in single genotypes, p=0.00001), suggesting varying clinical impacts based on immunocompromising conditions. Investigations into CMV infections and antiviral resistance mutations identified UL97 and UL54 mutations in 3.6% of renal transplant and 1.8% of HSCT recipients. The D605E mutation in UL97 was prevalent among renal transplant recipients (75% of cases with mutations) but showed no correlation with clinical characteristics. Analysis of CMV miRNAs revealed distinct expression patterns associated with infection stages in transplant recipients, highlighting their potential as molecular markers for disease progression. miR-UL148D, which modulates the TLR2/IRAK1/NFκB signalling pathway, exhibits increased expression during the late phase, suggesting a role in immune evasion and viral persistence. Similarly, miR- UL70-3p regulates apoptosis and immune modulation, contributing to viral persistence. Notably, miR-UL112-5p and miR-UL148D are upregulated during active infection, making them promising biomarkers for viral reactivation, while miR-UL70- 3p is associated with latent infection. Additionally, miR-UL22A-5p, miR-UL112-3p, and miR-US25-1-5p show consistent upregulation in active CMV infection, reinforcing their potential as universal biomarkers. These findings provide a foundational framework for understanding CMV miRNAs in transplantation and their clinical applications in disease monitoring and targeted therapies. Collectively, this study offers comprehensive insights into CMV epidemiology, risk factors, genetic diversity, resistance patterns, and miRNA expression in Malaysia, establishing a basis for improved diagnostics, targeted therapies, and enhanced management strategies for immunocompromised individuals.

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